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When studying for a doctoral degree (PhD), candidates submit a thesis that provides a critical review of the current state of knowledge of the thesis subject as well as the student’s own contributions to the subject. The distinguishing criterion of doctoral graduate research is a significant and original contribution to knowledge.
Once accepted, the candidate presents the thesis orally. This oral exam is open to the public.
Communication between the sympathetic nervous system (SNS) and the immune system maintains the body in homeostasis. There is direct release of hormones by the SNS where the T cells are located. The communication is achieved through adrenergic receptor (AR) expressed differentially in immune cells. Specifically, the β2AR is present on specialized immune cells from the adaptive immune system, T helper cells (Th). To elicit an immune response, these cells are activated by their unique T cells receptor (TCR) and co-stimulation provided by surface protein CD28 and cytokine milieu. The cells will differentiate, having unique features to target antigens with high specificity called Th1, Th2 and Th17 cells. In the context of adrenergic receptor, Th1 and Th2 cells are studied, however, little is known about Th17 cells. The aims of this thesis are to demonstrate the immunomodulatory effect of the β2AR on Th17 cells, in the context of proliferation, effect on differentiated cells, cell signalling and polymorphism of the β2AR gene cell response.
Human Th17 cells were demonstrated to express the β2AR and that it is functional. There was a reciprocal regulation between Th1 and Th17 cells observed, where the Th17 mediated response (IL-17A) was favoured. The majority of individuals samples tested showed an increase of IL-17A, where human variability plays a role. There was a link between common single nucleotides polymorphism on the gene for β2AR (ADRB2) and the IL-17A. The stimulation of the β2AR led to the activation of the signalling pathway mediated by protein kinase A (PKA). The activation of the PKA pathway challenges the paradigm where it is known to inhibit the TCR signalling, which is essential for the T cells to activate and deliver a proper immune response. The novel finding of the presence and functionality of β2AR on human Th17 cells, shows there is fine-tuning provided by the stimulation of β2AR that shifts the response towards an increase of IL-17A and diminished IFNγ. This report adds in comprehending how hormones released by the SNS and adrenergic drugs influence host protection mediated by Th cells through the β2AR.